Menopause is defined as the final episode of menstrual bleeding in women. The term is also used colloquially to refer to the period of time encompassing the transitional period between the reproductive years up to and beyond the final episode of menstrual bleeding. For the purposes of this invention, reference to menopause will encompass this transitional period. Menopause is the result of the cessation of follicular development, which leads to a drop in the production of estradiol and other hormones. While 60% of estrogen formed in pre-menopausal women is in the form of estradiol, most of which is produced in the ovaries of ovulating women, post-menopausal ovaries produce a minimal amount of estrogen, with extraglandular tissues providing the majority of post-menopausal estrogen synthesis.
Symptoms associated with menopause include vasomotor instability (hot flashes), a decrease in breast size, atrophy of the urogenital epithelium and skin, and osteoporosis, a disease which is characterized by a marked loss of bone mass. Hot flashes may be accompanied by nervousness, anxiety, irritability and depression. Osteoporosis and the decrease in size of the female reproductive tract and breasts have been closely correlated to low levels of estrogen, while the pathology of hot flashes, though less well understood, may also be related to the decrease in estrogen production accompanying menopause.
The significant loss of bone mass which occurs at the time of menopause ultimately gives rise to osteopenia, which in turn gives rise to spontaneous crush fractures of the vertebrae and fractures of the long bones. This disease is generally known as postmenopausal osteoporosis and presents a major medical problem, both in the United States and most other countries where the life-span of females reaches ages of at least 60 and 70 years. Generally the disease, which is often accompanied by bone pain and decreased physical activity, is diagnosed by one or two vertebral crush fractures with X-ray evidence of diminished bone mass. It is known that this disease is accompanied by diminished ability to absorb calcium, decreased levels of sex hormones, especially estrogen and androgens, and a negative calcium balance.
Methods for treating the disease have varied considerably but to date no really satisfactory treatment is yet being practiced. For example, calcium supplementation by itself has not been successful in preventing or curing the disease. Other treatments, for which variable results have again been reported, have included a combination of vitamin D in large doses, calcium and fluoride. The primary problem with this approach is that fluoride induces structurally unsound bone, called woven bone, and in addition, produces a number of side effects such as increased incidence of fractures and gastrointestinal reaction to the large amounts of fluoride administered.
Estrogen therapy is the most commonly used treatment of menopausal symptoms. Estrogen therapy ameliorates symptoms including hot flashes and atrophy of the urogenital epithelium and skin, and has positive effects on the incidence of osteoporosis.
Premarin is the most widely prescribed estrogen that is used for the treatment of postmenopausal symptoms, including osteoporosis, in the United States. Premarin is obtained from pregnant mares' urine, and contains the sodium salts of water-soluble estrogen sulphates as well as a variety of estrogen derivatives. One of the reasons that Premarin is so popular is because of concern that unconjugated estradiol, when given orally, has a first pass effect on the liver. This effect can have potentially serious consequences including the increase of blood clotting factors which can increase the user's risk of developing blood clots.
U.S. Pat. No. 4,225,596 discloses methods for treating or preventing metabolic bone disease characterized by the loss of bone mass by administering at least one compound having the formulae (I) and (II): ##STR1## where R.sub.1, R.sub.2 and R.sub.4 are each selected from the group consisting of hydrogen, hydroxyl, lower alkyl, acyl and O-alkyl and R.sub.3 is selected from the group consisting of hydrogen, hydroxyl, keto, lower alkyl, acyl and O-alkyl.
U.S. Pat. No. 4,410,515 discloses the following compounds having Formula (III) which are active in maintaining calcium and phosphorus metabolism and are useful for treating hypocalcemia in animals: ##STR2## wherein the bond between positions C-22 and C-23 is single or double; R.sup.2 is hydrogen, CH.sub.3 or CH.sub.2 CH.sub.3 ; X is selected from the group consisting of hydrogen and --OR.sup.1, where R.sup.1 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue; with the proviso that at least one of the R.sup.1 is glycosidic residue.
Fujimoro, et al. (Fujimoro et al., Experientia 42:567-568 (1988)) reported the biochemical synthesis of 17.beta.-estradiol-3-(.beta.-D-glucoside) and 17-(.alpha.-D-glucoside) by incubation of 17.beta.-estradiol with ovarian tissues from a silkworm. Similarly, incubation of 17.alpha.-estradiol 3-glucuronide with rabbit liver microsomes in the presence of uridine diphosphate glucose results in the synthesis of 17.alpha.-estradiol-17-(.beta.-glucoside). (Williamson et al., Biochemistry 8:45299-4304 (1969)). When 17.beta.-estradiol-17-glucoside and 17.alpha.-estradiol-17-glucoside were injected into normal women, the 3-glucuronide derivatives of each compound were recovered in the urine (Williamson et al., Canadian J. Biochemistry 50:958-962 (1972)).